Alzheimer's disease *AD) is a devastating neurological disorder characterized by a progressive dementia which affects 5-10% of the elderly over age 65. Genetic factors have clearly been implicated in the early and late-onset familial forms of the linked disease. A form of late-onset AD has been show to be linked to the proximal long arm of chromosome 19 and subsequently associated with Apolipoprotein E (ApoE). Apo E is a plasma apolipoprotein that is involved in lipid transport and metabolism. Apo E is produced in brain and found in three major isoforms in the human population which have been designated E2. E3. E4. These alleles occur at a frequency of approximately 8, 76, and 16 per cent, respectively. Recently, an association between the ApoE4 allele and an increased risk of late-onset AD has been established. Subsequent studies have demonstrated that Apo E2 has a protective effect or delays the age of onset of Ad. The exact mechanism by which the different isoforms exert their effects are as yet unknown. To study the mechanisms by which Apo E exerts its effects and the role which Apo E plays in brain molecular biology, physiology, and metabolism awe are creating Apo E 2. 3. and 4 transgenic mice. Cosmid libraries from human AD patients with the appropriate Apo E genotype were prepared in the cosmid vectors pWE15 and SuperCos 1. Apo E containing cosmid clones were isolated and restriction mapped. Clones of the proper size containing the brain expression control regions for Apo E were produced and purified. Experiments to produce Apo E transgenic mice using microinjection procedures will be carried out using ice which lack a functional Apo E gene (Apo E "knockout" mice). Mice, lacking a functional murine Apo E, will be produced which are homozygous and heterozygous for the human Apo E2, 3 and 4 alleles. These mice will serve as a model system for the study of the role of Apo E in brain function and metabolism and its potential role in Alzheimer's disease.